The objective is to produce findings that will be useful in the development of improved strategies for treating and preventing return to smoking, the primary cause of pulmonary and related metastatic disease. The specific aims are a) the generation of new and more definitive knowledge about the stimulus control of smoking/nicotine intake by environmentally-induced changes in affect; and b) specification of reinforcing consequences for smoking derived from the modulation of affect by nicotine. The project will focus upon the role of anxiety--a major motive for smoking, a putative reinforcer contributing to the entrainment of nicotine dependence, and a key factor in smoking relapse--over 4 years of research. In the first 3 years, anxiety induction and smoking/nicotine intake will be investigated in parametric laboratory studies, each using 20 subjects (male smokers scoring high on measures of addiction and anxiety factors) in repeated measures designs. The studies will involve different modes of anxiety induction (mental arithmetic or a film depicting bodily injury), different nicotine doses (using self-dosing with usual cigarettes or fixed-dosing with research cigarettes), and different initial levels of arousal (pretreatment with caffeine or a benzodiazepine). Subjective (withdrawal, alertness, anxiety, craving), physiological (heart rate, skin conductance), behavioral (smoking topography), and biochemical (cotinine, nicotine, norepinephrine, epinephrine, beta-endorphin) measures will be obtained. The resulting information, coupled with investigations involving nicotine-stimulated beta-endorphin release and naloxone-blocking of nicotine's anxiolytic effects, should permit identification of key functional relationships between anxiety and smoking. The fourth year of research will investigate, in 100 men and 100 women smokers scoring high on measures of addiction, individual differences in anxiety-susceptibility and resulting nicotine intake as predictors of ability to abstain from smoking in the ordinary environment, thus validating and extending the laboratory-based studies. (Inclusion of women in the final year was prompted by the suggestion that women's smoking-cessation rates lag behind those of men because of added difficulties in quitting due to greater anxiety-susceptibility or tension-reduction from smoking.) The resulting methodology may yield a means of testing new approaches to treatment and thus spur the development of more effective therapies for smokers with poor prognosis for quitting.